U.S. patent application number 14/451417 was filed with the patent office on 2016-02-04 for coherent blood coagulation structure of water-insoluble chitosan and water-dispersible starch coating.
The applicant listed for this patent is James F. Drake. Invention is credited to James F. Drake.
Application Number | 20160030623 14/451417 |
Document ID | / |
Family ID | 55178950 |
Filed Date | 2016-02-04 |
United States Patent
Application |
20160030623 |
Kind Code |
A1 |
Drake; James F. |
February 4, 2016 |
COHERENT BLOOD COAGULATION STRUCTURE OF WATER-INSOLUBLE CHITOSAN
AND WATER-DISPERSIBLE STARCH COATING
Abstract
An absorbent layer for moderating blood flow from a wound has a
non-woven fabric layer of water-insoluble chitosan fibers having a
coating of water-absorbent starch on at least one face of the
fabric layer. The coating of water-absorbent starch penetrates into
the fabric layer from a first surface over the chitosan fibers to a
depth of at least 25% of the fabric layer of chitosan fibers. The
chitosan fibers have average diameters of from 5 to 30 micrometers.
The average weight of starch/chitosan may decrease from the first
surface from which the starch has penetrated into the fabric to the
depth of at least 50% of the fabric layer. The starch may be
modified to include hydrophilic groups into or onto molecular
chains of the starch.
Inventors: |
Drake; James F.;
(Minneapolis, MN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Drake; James F. |
Minneapolis |
MN |
US |
|
|
Family ID: |
55178950 |
Appl. No.: |
14/451417 |
Filed: |
August 4, 2014 |
Current U.S.
Class: |
604/367 ;
424/445; 514/60 |
Current CPC
Class: |
B32B 27/32 20130101;
B32B 2255/02 20130101; B32B 27/322 20130101; B32B 2262/06 20130101;
B32B 5/22 20130101; A61L 15/42 20130101; B32B 5/145 20130101; B32B
27/12 20130101; B32B 27/40 20130101; B32B 5/022 20130101; A61L
15/28 20130101; B32B 27/283 20130101; B32B 2255/26 20130101; B32B
2307/728 20130101; A61L 15/28 20130101; A61L 15/425 20130101; B32B
9/02 20130101; B32B 2307/726 20130101; B32B 2535/00 20130101; B32B
5/26 20130101; A61L 2400/04 20130101; B32B 5/02 20130101; C08L 3/02
20130101; A61L 15/28 20130101; C08L 5/08 20130101; B32B 9/047
20130101 |
International
Class: |
A61L 15/28 20060101
A61L015/28; C08L 3/02 20060101 C08L003/02; C08L 5/08 20060101
C08L005/08; A61L 15/42 20060101 A61L015/42 |
Claims
1. An absorbent layer comprising a non-woven fabric layer of
water-insoluble chitosan fibers having a coating of water-absorbent
starch on at least one face of the fabric layer.
2. The layer of claim 1 wherein the coating of water-absorbent
starch penetrates into the fabric layer from a first surface over
the chitosan fibers to a depth of at least 25% of the fabric layer
of chitosan fibers.
3. The layer of claim 1 wherein the chitosan fibers have average
diameters of from 5 to 30 micrometers.
4. The layer of claim 1 wherein the chitosan fibers have average
diameters of from 8 to 25 micrometers.
5. The layer of claim 1 wherein the chitosan fibers have average
diameters of from 10 to 20 micrometers.
6. The layer of claim 2 wherein the chitosan fibers have average
diameters of from 8 to 25 micrometers.
7. The layer of claim 1 wherein the coating of water-absorbent
starch penetrates from a first surface into the fabric layer over
the chitosan fibers to a depth of at least 50% of the fabric layer
of chitosan fibers towards a second surface of the layer.
8. The layer of claim 4 wherein the coating of water-absorbent
starch penetrates from a first surface into the fabric layer over
the chitosan fibers to a depth of at least 50% of the fabric layer
of chitosan fibers towards a second surface of the layer.
9. The layer of claim 7 wherein average weight of starch/chitosan
decreases from the first surface from which the starch has
penetrated into the fabric to the depth of at least 50% of the
fabric layer.
10. The layer of claim 8 wherein average weight of starch/chitosan
decreases from one surface from which the starch has penetrated
into the fabric to the depth of at least 50% of the fabric
layer.
11. The layer of claim 1 wherein the starch has been modified to
include hydrophilic groups into or onto molecular chains of the
starch.
12. The layer of claim 2 wherein the starch has been modified to
include hydrophilic groups into or onto molecular chains of the
starch.
13. The layer of claim 7 wherein the starch has been modified to
include hydrophilic groups into or onto molecular chains of the
starch.
14. The layer of claim 8 wherein the starch has been modified to
include hydrophilic groups into or onto molecular chains of the
starch.
15. The layer of claim 10 wherein the starch has been modified to
include hydrophilic groups into or onto molecular chains of the
starch.
16. The layer of claim 1 carried on a structural support secured to
the second surface of the layer.
17. The layer of claim 2 carried on a structural support secured to
the second surface of the layer.
18. The layer of claim 7 carried on a structural support secured to
the second surface of the layer.
19. The layer of claim 14 carried on a structural support secured
to the second surface of the layer.
20. A method of mediating blood flow from a wound by applying the
first surface of a layer according to claim 1 against the wound
from which blood is flowing and clotting blood from the wound.
21. A method of mediating blood flow from a wound by applying the
layer according to claim 1 against the wound from which blood is
flowing and clotting blood from the wound.
22. A method of mediating blood flow from a wound by applying the
first surface of a layer according to claim 2 against the wound
from which blood is flowing and clotting blood from the wound.
23. A method of mediating blood flow from a wound by applying the
first surface of a layer according to claim 4 against the wound
from which blood is flowing and clotting blood from the wound.
24. A method of mediating blood flow from a wound by applying the
first surface of a layer according to claim 7 against the wound
from which blood is flowing and clotting blood from the wound.
25. A method of mediating blood flow from a wound by applying the
first surface of a layer according to claim 8 against the wound
from which blood is flowing and clotting blood from the wound.
26. The absorbent layer of claim 1 wherein the water-absorbent
starch coating is translucent to white light.
27. The absorbent layer of claim 1 wherein the water-absorbent
starch coating is transparent to white light.
Description
BACKGROUND OF THE ART
[0001] 1. Field of the Invention
[0002] The present invention relates to the field of blood control
at wound sites and coagulation of blood within a structure provided
at a wound site.
[0003] 2. Background of the Art
[0004] It has been recognized in the prior art that it is desirable
to stop bleeding by applying materials to the wound or tissue which
initiate or enhance blood coagulation. Such materials have included
collagen, gelatin, oxidized regenerated cellulose, kaolin,
polysaccharides such as starch or chitosan, liquid glues
(cyanoacrylate adhesives, gelatinous glues, UV curable polymers,
etc.) to name a few. Other materials which are made from human or
animal blood components such as thrombin, albumin and fibrinogen
have been used but carry the risk of virus infection and are
expensive to manufacture.
[0005] One method used to reduce bleeding involves initiating or
accelerate blood clotting by applying hygroscopic porous particles
directly to a wound. In this method the porous particles absorb the
water from blood allowing the natural fibrinogens within the blood
to coagulate, which results in a blood clot. The pore size of such
particles should be such that water is able to be readily absorbed
by the particles, but the clot forming blood components (thrombin,
fibrinogen, fibrin, platelets, etc.) are not. The size of the
pores, therefore, should be less than 1 micrometer (1,000 nm) and
preferably less than 0.1 micrometer (100 nm). The particles may be
made of many different materials, although it is preferable that
the materials be biocompatible and eventually absorbed by the body.
Another method in U.S. Pat. No. 4,822,349 (Hursey) describes the
use of zeolites, or molecular sieves, for accelerating clotting.
The zeolites are used in a particle form either as a powder poured
onto or into a wound, or embedded in a wound dressing. However,
while effective at adsorbing water from the blood and stopping
bleeding, this method suffers from several problems. Zeolites are
inorganic and are not readily absorbed by the body. This creates
significant difficulties in caring for the wound once the bleeding
is stopped. The zeolite particles, which have been placed in the
wound, must be debrided or scraped out of the wound once the
bleeding has stopped. This can be painful for the trauma victim and
require multiple surgical debridements. There is also an exothermic
reaction when water is adsorbed into zeolites that can cause the
temperatures at the wound site to reach 40.degree. C. to 50.degree.
C. or higher which can damage tissue and irritate the patient. Also
a significant number of people can have allergic reactions to the
zeolites. Another major concern is that the loose zeolite particles
can become entrained in a blood vessel where they will continue to
promote formation of clots. These small clots, which can then
circulate in the blood system, can potentially cause embolisms,
strokes, or other clot related problems. U.S. Pat. No. 6,060,461
(Drake) describes the use of particles made of porous materials
from within the classes of polysaccharides, cellulosics, polymers
(natural and synthetic), inorganic oxides, ceramics, zeolites,
glasses, metals and composites.
[0006] Polysaccharides are preferred because of their ready
availability and modest cost. They are widely known to be
biocompatible and are readily absorbed by the body over time.
Polysaccharides can be provided as starch, cellulose, and even
chitosan. Chitosan based wound dressings provided under the trade
names SoftSeal.RTM.-STF chitosan, Celox.TM. chitosan, "HemCon.RTM."
chitosan are all products based upon chitosan chemistry. The
chitosan is derived from chitin particles obtained from crustaceans
such as crab or shrimp. The particles can be applied in a powder
form directly to the wound, or held in place on the wound. However,
powders are difficult to apply, especially to wounds in which blood
is flowing since the powders can be washed away with the flowing
blood before clotting can be initiated.
[0007] A solution to problem of the powders washing away is
described in the Hursey and Drake patents wherein they embed or
attach the powders to a wound dressing. The wound dressing can take
the form of a sheet or film in which the particles are adhered to
or to the surface of fibers which make up woven or non-woven
gauze-like fabric or sheet. The particles can also be interspersed
with fibers, filaments or other particles in a self-supporting
structure, entangled within the fibrous elements of a net, web,
fabric or sheet. However, both the biocompatible particles and the
zeolite particles suffer the same problem in that they can become
entrained in the blood vessels and cause clotting related problems
in the blood vessels. While both of the Hursey and Drake patents
describe the use of a dressing with the particles embedded or
attached to a dressing for ease of application, there still exists
the danger of the particles shedding from dressing and becoming
entrained in the blood vessel and causing clotting within a blood
vessel. In addition, the use of a dressing made of one material
combined with the particles made of a different material increases
problems of biocompatibility and absorption. It also increases the
complexity of manufacturing and consequently manufacturing costs.
U.S. Pat. No. 3,620,218 (Schmitt) discloses a felt made of
polyglycolic acid fibers which may be used as a hemostat. However,
the felted fibers can float from a bleeding surface and are
generally too porous.
[0008] U.S. Pat. No. 3,937,223 (Roth) discloses an asserted
improvement upon U.S. Pat. No. 3,620,218 by compaction of the felt
on at least one side to provide strength and rigidity to the felt
as well as providing a smoother surface which can be drawn into
close conformity to the wound and thus reduce pockets in the felt
where blood or other fluids can accumulate. Roth uses filaments of
about 0.5 to 12 deniers per filament (approximately 7 um to 34 um)
and, conveniently, 2 to 6 deniers (approximately 14 um to 24 um)
per filament. These fibers are quite large and stiff which creates
large pores when made into a felt. To reduce the large pores one
compresses the felt to smoothen the surface of the felt and to
press the filaments closer together to create smaller pores between
the fibers and thereby enhance hemostatic properties of the felt.
However, even after compaction this technique suffers from the
large open regions or void volume. When the filaments are
compressed together, the void volume, or amount of open area
between fibers, is greatly reduced. The amount of open area between
fibers is important as the open area allows water to be wicked
between the fibers, leaving behind platelets and other clotting
agents, thus initiating the clotting process. The void volumes in
compressed and calendared felts are typically less than 70% and
usually less than 50%. The low void volumes in the felt reduces the
hemostatic effectiveness of the compressed felts since the wicking
of the water from the blood is a function of the surface area of
fibers in contact with the blood and the capillary effect created
by the pore size as well as the number of pores in the surface of
the media. In addition, to the less than optimal hemostatic
properties, the fibers in the felt which have not been compacted or
embossed are not bonded to the other fibers.
[0009] U.S. Pat. No. 8,063,264 (Spearman) discloses a wound
dressing and a method for enhancing the clotting comprising a
plurality of hydrophilic microfibers bonded to each other to form a
mat with the plurality of microfibers having a pore size
sufficiently small to inhibit wicking platelets from a wound into
the microfibers so that when applied to a wound the blood
coagulates and the microfibers remain external to the wound.
Another example of fiber matrix wound dressing for hemostasis is
U.S. Pat. No. 8,703,176 (Zhu).
[0010] U.S. Pat. No. 7,101,862 (Cochrum) provides hemostatic
compositions useful to promote hemostasis at active bleeding wound
sites. The hemostatic compositions typically include an article
containing cellulose, e.g., cotton gauze, and a polysaccharide
covalently linked to the cellulose, or a polysaccharide ionically
cross-linked and in association with the article. Methods of making
and using the hemostatic compositions are also provided.
[0011] U.S. Pat. No. 8,575,132 (Ji) describes a modified starch
material for biocompatible hemostasis, biocompatible adhesion
prevention, tissue healing promotion, absorbable surgical wound
sealing and tissue bonding, when applied as a biocompatible
modified starch to the tissue of animals. The modified starch
material produces hemostasis, reduces bleeding of the wound,
extravasation of blood and tissue exudation, preserves the wound
surface or the wound in relative wetness or dryness, inhibits the
growth of bacteria and inflammatory response, minimizes tissue
inflammation, and relieves patient pain. Any excess modified starch
not involved in hemostatic activity is readily dissolved and rinsed
away through saline irrigation during operation. After treatment of
surgical wounds, combat wounds, trauma and emergency wounds, the
modified starch hemostatic material is rapidly absorbed by the body
without the complications associated with gauze and bandage
removal.
[0012] All referenced cited herein are incorporated by reference in
their entirety.
SUMMARY OF THE INVENTION
[0013] An absorbent layer for controlling or moderating blood flow
from a wound has a non-woven fabric layer of water-insoluble
chitosan fibers having a coating of water-absorbent starch on at
least one face of the fabric layer. The coating of water-absorbent
starch penetrates into the fabric layer from a first surface over
the chitosan fibers to a depth of at least 25% of the fabric layer
of chitosan fibers. The chitosan fibers have average diameters of
from 5 to 30 micrometers. The average weight of starch/chitosan may
decrease from the first surface from which the starch has
penetrated into the fabric to the depth of at least 50% of the
fabric layer. The starch may be modified to include hydrophilic
groups into or onto molecular chains of the starch.
BRIEF DESCRIPTION OF THE FIGURES
[0014] FIG. 1A is a scanning electron micrograph (SEM) of a
nonwoven chitosan fiber matrix without any added starch. The view
is a top view of the fiber mat. The magnification is 20.times..
[0015] FIG. 1B is an electron micrograph (SEM) of a nonwoven
chitosan fiber matrix without any added starch. The view is a top
view of the fiber mat. The magnification is 20.times..
[0016] FIG. 2A is a light micrograph (LM) of nonwoven chitosan
fiber matrix without any added starch. The view is an edge view of
the fiber mat. The magnification is 25.times..
[0017] FIG. 2B is a light micrograph (LM) of nonwoven chitosan
fiber matrix without any added starch. The view is a top view of
the fiber mat. The magnification is 25.times..
[0018] FIG. 3A is a scanning electron micrograph (SEM) of a
nonwoven chitosan fiber matrix with an additional coating of
starch. The view is a top view. The magnification is 20.times..
[0019] FIG. 3B is a scanning electron micrograph (SEM) of a
nonwoven chitosan fiber matrix with an additional coating of
starch. The view is a top view. The magnification is
100.times..
[0020] FIG. 4A is a light micrograph (LM) of nonwoven chitosan
fiber matrix with an additional coating of starch. The view is a
top view of the fiber mat. The magnification is 25.times..
[0021] FIG. 4B is a light micrograph (LM) of nonwoven chitosan
fiber matrix with an additional coating of starch. The view is a
top view of the fiber mat. The magnification is 67.times.. The
image shows the transparency/translucency to white light of the
modified starch coating and transparency/translucency to white
light of the underlying chitosan fabric substrate.
[0022] FIG. 5 is a schematic representation of a cutaway side view
of the chitosan fiber matrix similar to that of FIGS. 3A and 3B
emphasizing distribution of the starch layer 106a from one surface
102 into the non-woven chitosan 104. Remembering that this FIG. 5
is an illustrative rendition and is not intended to be a limiting
description of distribution of materials, thicknesses and rheology
of layers, it can be seen that in Zone 1, there is a heavier
thickness 106 of the starch coating 106a. In Zone 2, there is a
thinner coating 108 of the starch coating 106a. In Zone 3, there
tends to be a more discontinuous coating 110 of the starch coating
106a. In Zone 4, there is essentially no starch coating 106a in
this rendition. There are open volumes 112 between the coated 106a
chitosan fibrous elements 104 within the matrix 100. The
distribution is illustrative of how materials are likely to be
distributed from a single side (through surface 102) application of
the starch coating 106a. Different methods of application (e.g.,
two-side application, dipping, pressure-coating, spray coating,
meniscus coating and the like) will create varying patterns if
starch distribution within the matrix 100. For example, with two
side coating application of the starch, a complete cross-section
distribution might look more like a mirror image of Zone 1, Zone 2,
Zone 2 again and Zone 1 again (in order) so that there is a
relatively continuous, though varying in thickness, coating of
starch across the entire thickness of the matrix. It might also be
possible to have mirror cross-sections of a) Zone 1, Zone 2, Zone
3m Zone 2, Zone 1, or b) Zone 1, Zone 2, Zone 3, Zone 4, Zone 3,
Zone 2 and Zone 1, Not only the thickness of the starch coating 106
may vary across the thickness of the fabric, but also the coating
weight per volume will vary and the coating weight variations (in a
two-side coated matrix) may be different from one surface versus
the other surface.
[0023] FIG. 5A is an SEM of Chitosan-STF fibers machine coated with
starch. The magnification is 100.times..
[0024] FIG. 5B is a LM of Chitosan-STF fibers machine coated with
starch. The magnification is 67.times..
[0025] FIG. 6A is an SEM of Chitosan-STF fibers machine coated with
starch The magnification is 50.times..
[0026] FIG. 6B is an LM of Chitosan-STF fibers machine coated with
starch. Magnification is 33.times..
DETAILED DESCRIPTION OF THE INVENTION
[0027] An absorbent layer has a non-woven fabric layer of
water-insoluble chitosan fibers having a coating of water-absorbent
starch on at least one face of the fabric layer. The coating of
water-absorbent starch may penetrate into the fabric layer from a
first surface over the chitosan fibers to a depth of at least 25%
of the fabric layer of chitosan fibers towards a second surface.
The chitosan fibers may have average diameters (not lengths) of
from 5 to 30 micrometers, 8 to 25 micrometers or 10 to 20
micrometers. The fibers may have aspect ratios of from 1.5 to 50
(or more if continuous fibers). The average weight of
starch/chitosan decreases from the first surface from which the
starch has penetrated into the fabric to the depth of at least 50%
of the fabric layer. The decrease may be graded (e.g., nominally
from a 60/40 starch to chitosan at the surface region (e.g., the
first 10% of depth) to a nominal 10/90 ratio). The gradation may be
straight-line linear or slower drop=off or faster drop-off
depending upon methodology of applying the starch and/or
intentional design. The coating may be on only one side of the
layer or may be applied from both sides to provide an asymmetric
distribution or symmetric distribution, respectively.
[0028] The starch component of the layer, as described in greater
detail herein may be a starch that has been modified to include
hydrophilic groups attached onto molecular chains of the starch.
The layer may be carried on a structural support secured to the
second surface of the layer.
[0029] A method is provided herein of mediating blood flow from a
wound by applying the first surface of a layer according to the
present technology against the wound from which blood is flowing
and clotting blood from the wound.
[0030] Chitin is recovered from crab shells by treatment with acid
to remove the minerals and with alkali to remove protein. After
these treatments, purified chitin remains as thin, white sheets
that are further processed into chitosan. Chitosan is made by
heating purified chitin with strong alkali to remove some of the
acetyl groups from the polymer chains. These exposed amino groups
have a positive (also known as cationic) charge in water or dilute
acid. When 50% or more of the amino groups have been exposed the
material becomes soluble in water or dilute acid due to the
repulsion of the charged groups along the polymer chain. Thus,
chitosan is defined as a derivative of chitin in which 50% or more
of the amino groups are exposed or the chemical term is
deacetlylated.
[0031] Starch is produced by all green plants and is stored for
future energy use by the plant in their leaves, roots, and seeds.
Commercial raw starch is obtained from corn, potato, rice, wheat
and other seed or tuber crops. The raw starch is insoluble in water
and is not efficacious as a hemostatic agent. Raw starch must be
modified to increase its hydrophilicity. The modification process
may be completely physical, chemical or a combination of the two.
In general, raw starch is treated with water and heat to swell the
raw starch granules and convert the material to a gelatinous mass.
Further physical treatment such as extrusion or roll processing can
be used to increase the hydrophilicity. After heating the raw
starch with a measured amount of water, starch granules swell to a
pasty substance, regularly arranged micelles of starch are broken,
crystallites disappear, and the resulting composition is easily
degraded by amylase. The pre-gelatinized starch is able to swell
and/or dissolve in cold or room temperature water and form an
adhesive paste whose tendency for retrogradation is lower than that
of raw starch, affording easier handling during the production
process.
[0032] The present technology uses water dispersible or
water-soluble starch. Where the term starch is used with reference
to the starch coatings according to the present technology the term
starch is defined and limited to water-soluble, water-dispersible
and/or gelatinized starches as known in the art. The modified
starch may be either physically and/or chemically modified as
described herein.
[0033] Gelatinized Starch Further Modified by Chemical
Treatment.
[0034] Physically modified starch, for example, a pre-gelatinized
starch treated solely with spray drying or irradiation process, is
remarkably safe as a bio-absorbable, hemostatic material since it
is not treated with any chemical agents and is readily degraded by
enzymes present in the tissues.
[0035] Chemical modification of the starch polymer chains can
further enhance the hydrophilicity of the gelatinized starch. The
hydroxyl groups on the glucose monomers of starch can be reacted
with a wide variety of chemical agents in order to introduce
chemical functionality that can significantly increase the
attraction of the starch for water. It has been found that
introduction of carboxymethyl, hydroxyethyl or hydroxypropyl groups
are particularly useful. Other useful modifications include
phosphate esterification, and cross-linking using bifunctional
agents such as epichlorohydrin. A complete discussion of the many
possible modified starches useful as hemostatic agents is found in
U.S. Pat. No. 8,575,132 (Ji).
[0036] When applied to a bleeding wound, the hemostatic efficacy of
a particular starch composition is affected by both the water
absorption characteristics (hydrophilicity) and the viscosity of
the resulting starch-blood composition. The hemostatic properties
of a particular modified starch depend upon, first, the
characteristics of the raw starch, such as molecular weight of the
starch polymers, and the relative amounts of amylose and
amylopectin in the raw starch; and, second, modifications made to
the particular starch by chemical treatments such as
carboxymethylation or hydroxymethylation. U.S. Pat. No. 8,575,132
provides a useful discussion of the parameters found useful in
preparing hemostatic starch compositions. In particular, a
molecular weight range of 15,000 to 2,000,000 Daltons, a water
absorption capacity ranging from greater than one gram of water per
gram of modified starch to 500 grams of water per gram of modified
starch, and inclusion of at least one carboxymethyl starch or one
hydroxymethyl starch were found useful in preparing efficacious
hemostatic compositions. These compositions, when contacting blood,
produce a "starch-blood coagulation matrix" that has strong
adhesive characteristics which can seal wounded tissue and stop
bleeding. In addition, the interaction between the formed blood
coagulation matrix and the functional groups of tissue proteins
causes the "starch-blood coagulation matrix" to adhere to and seal
the wounded tissue, resulting in hemostasis.
[0037] Other biocompatible hemostatic materials that may be added
to the modified starches can comprise one or more of the groups of
gelatin, collagen, carboxymethyl cellulose, oxidized cellulose,
oxidized regenerated cellulose, and chitosan. The weight ratio
between the modified starch and any other biocompatible hemostatic
materials preferably is: 95:5, 90:10, 85:15, 80:20, 75:25, 70:30,
65:35, 60:40, 55:45, 50:50, 45:55, 40:60, 35:65, 30:70. This
additional coagulant material may be added to the described
modified starch hemostatic material before or during the vacuum
freeze drying production process to produce a composite hemostatic
composite. The production process may involve, but is not limited
to, pre-mixing the coagulant material with the modified starch
directly before any vacuum freeze drying process. The coagulant of
the present invention comprises one or more combinations of the
following group of blood coagulation factors: thrombin, fibrinogen,
or calcium salts. The topical application of the layer of chitosan
and modified starch can be used as a hemostatic agent to manage and
control bleeding wound surfaces in humans, mammals, birds, or
reptiles. Another advantage of the class of modified starch
hemostatic material described herein is the rapid particle
dispersion/dissolution in water, facilitating both the easy
deposition of the starch onto the chitosan fabric material and the
easy removal of excess modified starch particles from the wound by
simple saline irrigation. The residual modified starch not actively
involved in hemostasis can be rinsed away by irrigation. In the
treatment of battle wounds, self rescue, or first aid, the
hemostatic material remaining in small amounts will be absorbed by
the body and the irritation of wound debridement or gauze removal
is avoided.
[0038] The chitosan/modified starch hemostatic material has
properties of stability, extended shelf life, resistance to high
and low pressure, resistance to high temperatures up to 60 C and
low temperatures down to -40.degree. C., convenient storage, and
physical stability. Therefore, it may also be employed as a
hemostatic material for the military, emergency, and first-aid
uses. Particularly, it can be adapted for extreme environmental
conditions such as desert areas, polar regions, alpine areas, outer
space, and underwater probes.
[0039] The chitosan/modified starch compositions are pliable and
flexible. Therefore, they can be conformed to r wound surfaces with
various shapes, sizes, and features, such as deep and irregular
traumatic wounds. The chitosan/modified starch compositions
contemplated here are easily sterilized using gamma irradiation,
ultraviolet radiation, oxirane or ozone sterilization. Chemical
treatments and addition of chemicals and elements (e.g., organic
antimicrobials iodine, cupric ion, silver particles, etc.) may
further sterilize or may retain antimicrobial activity of the
coated material. Such additions may be made during or after
manufacture of the structure.
[0040] One example of a production process for a biocompatible
modified starch material useful in the present invention,
comprising the steps of: First, providing a modified hygroscopic
biocompatible starch material and loading it into an agglomerating
apparatus under 40.about.50.degree. C.; and
[0041] Second, adding distilled water and producing a modified
starch finished product material by particle agglomerating and
pellet processing. The modified starch finished product material
has a molecular weight over 15,000 Daltons (for instance, 15,000 To
about 2,000,000 Daltons) and a grain diameter of 10-1000 .mu.m,
wherein starch grains with diameters of 30-500 .mu.m represent no
less than 95% of the total amount of starch grains. The modified
starch material according to the present invention can be applied
as a suspension in water or other solvents or as adry powder to a
preformed layer of chitosan, which may or may not already be
self-supporting. The layer may be made self-supporting by the
coalescing of the aqueous (or organic solution such as alcoholic)
solution or dispersion of the starch onto at least one surface of
the chitosan layer. The chitosan/modified starch layer according to
the present invention can be used on soft tissue and organs to
rapidly and effectively control bleeding.
[0042] As noted herein, the chitosan/modified starch layer may be
provided in a structure having additional layers associated into a
final structure. For example, on multi-layer structure contemplated
is [0043] 1) A multilayer pad; [0044] 2) Exterior layer has fabric
of chitosan/modified starch fabric; [0045] 3) Optionally separated
by freeze dried starch sheet; [0046] 4) At least one exterior
chitosan fabric layers (as many as three) and separate internal
starch layers [0047] as carrier layers bound to chitosan layers.
[0048] 5) An optional support layer comprised of a polymeric or
similarly elastic material. An example is polypropylene,
polyurethane, polytetrafluoroethylene, or silicone
[0049] A preferred structure as enabled above would have the fiber
layer composition formed from chitosan fibers which are insoluble
in water and starch particles which are soluble, or mostly soluble
in water. The chitosan fibers are preferably 10 to 20 micrometers
in diameter. The starch material (which is commercially available
from Starch Medical, Inc.) is comprised mostly of carboxymethyl
starch and is soluble and/or swellable in water. There is
preferably no intentional cross-linking of either chitosan or
starch.
[0050] An underlying concept of one aspect of the present
technology is to combine the chitosan fibers, which exert a
hemostatic effect by virtue of a positive charge on the fiber
surface interacting with the negative charge on the surface of red
blood cells and platelets, with a starch-based hemostat to get a
synergistic effect. The combination products show better results
than either product alone.
[0051] The chitosan fibers and the starch powder could be combined
as a dry mix (and preferably exposed to moisture to assure securing
the modified starch to the chitosan fibers) and some tests show
that this will work. It is preferred to make a stable, reproducible
formulation by coating the chitosan fibers with a
solution/suspension of starch and drying the composite.
[0052] The chitosan layer (having the fibers bound or loosely
associated) then has the at least one-side coating of the modified
starch applied as by dip-coating, roller coating, spray coating,
meniscus coating, slot coating, brush coating or the like. The
gradation and depth of penetration of the applied modified starch
liquid composition is controlled by viscosity, density,
concentration and properties of the solution in combination with
the particular coating techniques and rate and volume of
application of the composition, as well as drying and pressure
application parameters.
[0053] Water-soluble starches may be provided according to numerous
technologies and sources, including at least U.S. Pat. No.
4,076,663 (Masuda) in which a highly water-absorbent resin is
produced by polymerizing (A) starch or cellulose, (B) at least one
monomer having a polymerizable double bond which is water-soluble
or becomes water-soluble by hydrolysis and (C) a crosslinking
agent, and subjecting, if necessary, the resulting product to
hydrolysis; U.S. Pat. No. 6,833,488 describing a bio-compatible,
biodegradable macromolecular water-absorbent polymeric material
having a three-dimensional configuration with intermolecular
covalent bonds and containing free functional groups selected from
OH, SH, NH.sub.2, and COOH. The polymer is formed by
polymer-polymer inter-coupling interaction between a natural
water-soluble polymer A or its derivatives having a molecular
weight between 20,000 and 500,000 Da, and a synthetic polymer B in
a ratio of A:B of 15:85 to 85:15; U.S. Pat. No. 8,710,212 Thibodeau
describing an absorbent material consisting of a molecular network
of starch molecules, the starch molecules comprising an amylopectin
content of at least 90% (w/w). The molecular network can either be
comprised of self-entangled starches or cross-linked starches;
Description of Chitosan and Chitosan-STF
[0054] U.S. Pat. No. 8,703,176 (Zhu) describes a unique and
proprietary chitosan structure and formulation. The structure is a
nonwoven fleece made from high molecular weight chitosan fibers
that offers a significant improvement in hemostasis performance and
reliability. This material provides a strong technology platform
that can be used to create a family of products each with its own
indications for use. Commercial hemostatic products using this
technology are produced by Chitogen Inc.
[0055] Chitosan is a polymer, soluble in water or dilute acid, made
from chitin by chemical treatment. Chitin is an abundant natural
product that is the primary structural material in the shells of
shrimp, lobsters and other crustaceans. Chitin's structural role in
shells is similar to the role of
##STR00001##
cellulose in plants. Both chitin and cellulose are high molecular
weight polymers containing glucose molecules linked together to
form long, linear polysaccharide chains.
[0056] Chitin is recovered from the crab shell by treatment with
acid to remove the minerals followed by treatment with alkali to
remove protein. After these treatments, purified chitin remains as
thin, white sheets that are further processed into chitosan.
Chitosan is made by heating purified chitin with strong alkali (40%
sodium hydroxide) to remove some of the acetyl groups from the
polymer chains. These exposed amino groups have a positive (also
known as cationic) charge in water or dilute acid. When 50% or more
of the amino groups have been exposed the material becomes soluble
in water or dilute acid due to the repulsion of the charged groups
along the polymer chain. Thus, chitosan is defined as a derivative
of chitin in which 50% or more of the amino groups are exposed or
the chemical term is deacetlylated.
[0057] Hemostatic products made from chitosan (SoftSeal.RTM.-STF,
Chitogen Inc) are non-woven pads composed of chitosan fibers
attached to a thin polypropylene backing material. The pad is
intended to be used as an aid in the management of topical bleeding
wounds such as vascular access sites and topical lacerations.
[0058] The principle of operation of chitosan-based products is
believed to result from bioadhesion between the chitosan polymer
chains (positive charge) and blood and tissue components (negative
charge) as well as pressure related tamponade. The charge density
and uniformity of the positive charge is enhanced by the surface
treated fiber (STF) process as described by U.S. Pat. No.
8,575,132.
Example
Description of Duplex Formulation
[0059] Chitosan fibers (Soft-Seal-STF, Chitogen Inc) were coated
with carboxymethyl starch (AMP-66, Starch Medical) using an airless
spray technology and the resulting duplex structures were evaluated
using a recognized animal bleeding model.
[0060] Chitosan fibers were spray-coated with two levels of
modified starch. Carboxymethyl starch, 5.0 or 10 grams was
dissolved in 600 ml of 5% acetic acid. The spray coating was done
by hand control using a spray painter (home use) held approximately
12 inches from the fabric which was placed on a paper background.
The sprayer was activated for a total of three passes and total
exposure time was approximately 2 to 3 seconds. The sprayed
chitosan fibers were air-dried overnight and placed into a zip-lock
bag. No evidence of leakage from the sprayed material was
observed.
[0061] The ability of the two prototypes to control bleeding and
their adherence to the bleeding surface was assessed. These studies
investigated the rapid control of bleeding using a hold or
compression times of 1 minute or 2 minutes used to determine
hemostatic performance from the bleeding soft organ.
[0062] In both the 5 and 10 gram starch solutions, coated fibers
were observed on the surface of the fiber mat with uncoated fibers
in the depths of the mat.
[0063] FIG. 5 is a schematic representation a cutaway side view of
the chitosan fiber matrix 100 similar to that seen in FIGS. 3A and
3B emphasizing distribution of the AMP layer 106a from one surface
102 into the non-woven chitosan 104. Remembering that this FIG. 5
is an illustrative rendition and is not intended to be a limiting
description of distribution of materials, thicknesses and rheology
of layers, it can be seen that in Zone 1, there is a heavier
thickness 106 of the starch coating 106a. In Zone 2, there is a
thinner coating 108 of the starch coating 106a. In Zone 3, there
tends to be a more discontinuous coating 110 of the starch coating
106a. In Zone 4, there is essentially no starch coating 106a in
this rendition. There are open volumes 112 between the coated 106a
chitosan fibrous elements 104 within the matrix 100. The
distribution is illustrative of how materials are likely to be
distributed from a single side (through surface 102) application of
the starch coating 106a. Different methods of application (e.g.,
two-side application, dipping, pressure-coating, spray coating,
meniscus coating and the like) will create varying patterns if
starch distribution within the matrix 100. For example, with two
side coating application of the starch, a complete cross-section
distribution might look more like a mirror image of Zone 1, Zone 2,
Zone 2 again and Zone 1 again (in order) so that there is a
relatively continuous, though varying in thickness, coating of
starch across the entire thickness of the matrix. It might also be
possible to have mirror cross-sections of a) Zone 1, Zone 2, Zone
3m Zone 2, Zone 1, or b) Zone 1, Zone 2, Zone 3, Zone 4, Zone 3,
Zone 2 and Zone 1, Not only the thickness of the starch coating 106
may vary across the thickness of the fabric, but also the coating
weight per volume will vary and the coating weight variations (in a
two-side coated matrix) may be different from one surface versus
the other surface,
Animal Test Results
Experiment #1
[0064] The soft organs of a live pig were selected for a bleeding
model to test the efficacy of the preparations. A 6 mm biopsy punch
that was inserted to a depth of approximately 6 mm to create
circular incisions in both the liver and spleen of the pig. The
test material was applied and held for one minute for liver
incisions and two minutes for spleenic incisions. The bleeding
model is described in detail in the protocol is XVE004, from
American Preclinical Services, Minneapolis, Minn. The duplex
formulations of chitosan fiber and modified starch at the 5 gram
and 10 gram level showed superior performance to the chitosan fiber
control. There was less bleed through at the 1 minute hold for the
liver and 2 minute hold for the spleen. It was determined that the
1 minute hold although adequate for the liver was insufficient for
the spleen.
[0065] This bleeding model was a very severe test for hemostatic
pads. A hold time of one or two minutes although useful for the
animal model is not specifically intended to predict use in
clinical situations.
[0066] In this particular study, we observed an improvement in
hemostatic performance for the 10 gram material when compared to
the lower concentration, 5 grams. However both were an improvement
compared to the plain STF and thus the three concentrations (zero,
0.8% and 1.7% grams/ml) provide a clear dose response trend.
[0067] The chitosan fiber/modified starch composition was folded
over to provide a double thickness layer. This configuration was
also tested in the more demanding spleen bleeding sites and was
found to be very effective. In contrast, the control chitosan fiber
pad alone when doubled up did not achieve an improved hemostatic
control.
[0068] These experiments show that a single layer of chitosan
fibers, coated with modified starch provide an improved hemostatic
pad for topical, percutaneous injury. For more severe bleeding, the
use of multiple layers is preferred.
Experiment #2
[0069] Using the same materials and method as used for Example 1, a
new set of starch fiber pads coated with modified starch was
prepared
[0070] The pads were tested in the same animal bleeding model.
[0071] Light microscope and scanning electron microscope images are
shown in Figure YYY
[0072] Wounds treated with pads of chitosan fibers coated with
modified starch oozed less than the chitosan fiber pads alone.
Oozing is defined as blood leaking from the edge of the wound after
the pad is applied and held in place for one or two minutes. Such
oozing is considered a failure to control the bleeding from the
wound.
[0073] Using the liver and the spleen we tested 19 chitosan fiber
pads (control) and 18 pads of chitosan fiber coated with modified
starch. Both groups exhibited good hemostatic performance but for
the control pads there were 4 that oozed (failed). That is 4/19=21%
showed some blood leakage. For the chitosan fibers coated with
modified starch there were no failures. Using Fisher's Exact Test
to compare these results we calculate that the probability of these
results being due to chance is 0.056.
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